Transmissible spongiform encephalopathies (TSEs) include scrapie in sheep; bovine spongiform encephalopathy (BSE) in cattle; chronic wasting disease (CWD) in deer and elk; and Kuru and Creutzfeldt-Jakob disease in humans. Accumulation of PrPRES, a proteinase K (PK) resistant form of the normal prion protein, PrPC appears central to the pathogenesis of these diseases. TSEs are invariably fatal diseases for which no early diagnosis or treatment exists. RNA interference (RNAi), a relatively new discovery in both plants and animals that regulates the amount of RNA available for translation into protein, has been used experimentally to limit the amount of viral, bacterial and cancer cell replication. Recent advances toward an effective therapy for prion diseases employ RNAi to suppress expression of a normal host protein, PrPC, in neurons and subsequent prion neuropathology, exploiting the phenomenon that disease severity and progression correlate with the amount of PrPC present in neurons. However, delivery of lentivirus encoding PrP short hairpin RNA for RNAi has demonstrated only modest effectiveness experimentally and limited use clinically due to the invasive delivery method, limited area and irreversibility of PrPC suppression and safety concerns. We have recently developed a novel small interfering RNA (siRNA) delivery system using liposome-siRNA-peptide complexes (LSPCs) to protect siRNAs from serum degradation, deliver siRNA specifically to neurons and knockdown PrPC sufficiently to cure prion disease in two cell culture models. Here we propose to extend this work to cure two distinct prion diseases in mice using LSPCs injected intravenously (iv) to deliver PrP siRNA across the blood-brain-barrier (BBB) to neurons throughout the brain. Our specific aims are as follows. SPECIFIC AIM 1: Determine kinetics of LSPC delivery and PrPC knockdown in mice to optimize LSPC therapy to treat prion disease SPECIFIC AIM 2: To determine whether PrP siRNA-containing LSPCs can cure established prion infection in mouse models of scrapie and chronic wasting disease (CWD) a. Infect mice with mouse-adapted strains of scrapie and CWD prions b. Monitor mice for early behavioral and cognitive defects prior to onset of clinical diseas c. Treat mice with PrP and control LSPCs using regiments varying in dosage and timing PUBLIC HEALTH RELEVANCE: Prion and other neurodegenerative diseases such as Alzheimer's disease are devastating illnesses that greatly impact public health, agriculture and wildlife in North America and around the world. These diseases invariably result in death, so finding an effective therapy to treat these diseases would greatly improve the well-being of humans and wildlife.